Synthesis of 24,24-Difluoro-1,3-cis-25-dihydroxy-19-norvitamin D3 Derivatives and Evaluation of Their Vitamin D Receptor-Binding Affinity

Tanima Biswas; Yusuke Akagi; Kosuke Usuda; Koji Yasui; Isao Shimizu; Mayumi Okamoto; Motonari Uesugi; Seijiro Hosokawa; Kazuo Nagasawa

doi:10.1248/bpb.b16-00316

Notes

Synthesis of 24,24-Difluoro-1,3-cis-25-dihydroxy-19-norvitamin D₃ Derivatives and Evaluation of Their Vitamin D Receptor-Binding Affinity

Tanima Biswas, Yusuke Akagi, Kosuke Usuda, Koji Yasui, Isao Shimizu, Mayumi Okamoto, Motonari Uesugi, Seijiro Hosokawa, Kazuo Nagasawa

Author information

Tanima Biswas
Faculty of Advanced Science and Engineering, Waseda University
Yusuke Akagi
Graduate School of Technology, Tokyo University of Agriculture and Technology
Kosuke Usuda
Graduate School of Technology, Tokyo University of Agriculture and Technology
Koji Yasui
Graduate School of Technology, Tokyo University of Agriculture and Technology
Isao Shimizu
Faculty of Advanced Science and Engineering, Waseda University
Mayumi Okamoto
Faculty of Advanced Science and Engineering, Waseda University
Department of Immunology and Pathology, Research Institute, National Center for Global Health and Medicine
Motonari Uesugi
Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University
Institute for Chemical Research, Kyoto University
Seijiro Hosokawa
Faculty of Advanced Science and Engineering, Waseda University
Kazuo Nagasawa Corresponding author
Graduate School of Technology, Tokyo University of Agriculture and Technology

Keywords: 24,24-difluoro-19-norvitamin D₃, vitamin D receptor binding, cis-A ring synthon, vitamin D, Julia–Kocienski coupling

JOURNAL FREE ACCESS FULL-TEXT HTML

2016 Volume 39 Issue 8 Pages 1387-1391

DOI https://doi.org/10.1248/bpb.b16-00316

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Abstract

Two vitamin D₃ derivatives, namely 24,24-difluoro-1β,3β,25-dihydroxy-19-norvitamin D₃ (6a) and 24,24-difluoro-1α,3α,25-dihydroxy-19-norvitamin D₃ (6b), were synthesized via a convergent route employing Julia–Kocienski olefination as a key step. Compounds 6a and b bound to vitamin D receptor (VDR) with IC₅₀ values of 64.8 and 57.6 nM, respectively, exhibiting about 400- and 30-fold greater binding affinity than the corresponding non-fluorinated derivatives 5a and b.

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